Conventionally, steroid or indomethacin is administered after an entoptic operation of cataract, corpus vitreum, glaucoma or the like, for the reason that fibrin is formed with considerable frequency to cause postoperative complications. However, administration of said compounds for a few weeks after the operation has not shown dependable effects, but causes, though not often, delay in healing of wounds or disorders in cornea.
Fibrin is formed from fibrinogen by the cleavage of arginine-glycoside linkage of fibrinogen by thrombin. Since the aforementioned arginine amide has a potent selective antithrombin action (Japanese Patent Publication No. 48829/1986), the compound is expected to be useful as an eye drop or entoptic perfusate to inhibit formation of fibrin in an entoptic operation.
Taking one of the aforementioned arginine amides, (2R,4R)4-methyl-1-[N.sup.2 -((RS)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piper idinecarboxylic acid monohydrate (generally called argatroban) as an example, it is used at a concentration of 1 mg/ml or above as an eye drop or entoptic perfusate for the above-mentioned purpose. Said argatroban has an extremely low solubility in water, showing about 0.9 mg/ml of solubility at 25.degree. C. in the pH range (7.2-7.8) preferable for the administration to local eye sites. Hence, it is necessary to improve the solubility and, as a consequence, the usefulness of argatroban as a medicament. While an aqueous solution of argatroban can be preserved stably in a brown bottle, an improved stability thereof will result in a still greater utility of argatroban as a medicament.
Heretofore, arginine amides are known to be dissolved by a method including addition of sugar and alcohol (U.S. Pat. No. 5,214,052).
In view of the extremely high sensitivity to irritation that the local eye sites such as cornea exhibit, such method of adding sugar and alcohol is not desirable, since sugar and alcohol per se are irritant to the eye and these compounds are added in greater amounts. Consequently, there is practically no aqueous agent satisfactory as an eye drop or an entoptic perfusate containing arginine amide, particularly argatroban.
An object of the present invention is to provide an aqueous agent containing arginine amide improved in the effective utility as a medicament, particularly an aqueous agent of arginine amide having an improved solubility and an aqueous agent of arginine amide showing an improved stability.
Another object of the present invention is to provide a method for improving the effective utility of arginine amide as a medicament in an aqueous agent thereof, specifically a method for improving the solubility of arginine amide and a method for achieving a high stability thereof.